Finding new antibiotics: A specialised area of drug discovery

Ashleigh Paparella, post-graduate researcher in the structural biology and drug design lab, at the University of Adelaide, talks about the challenges that antimicrobial resistance poses and possible ways around it

Following the discovery and mass distribution of penicillin more than 70 years ago, antibiotics have been phenomenally successful in reducing the morbidity and mortality associated with bacterial infections.

However, we are in serious danger of entering a post-antibiotic era due to the alarming rise in antibiotic resistance.

The World Health Organisation has labelled antibiotic resistance as a global threat to human health and recently, researchers have discovered bacteria that are resistant to the last-line drug colistin.

These alarming findings indicate that bacteria have now acquired resistance to every antibiotic currently available.

Most of the antibiotic classes in clinical use today were discovered during the 1940s-1960s in the golden era of antibiotic discovery. Since then the discovery and development of new agents has slowed considerably with only 4 new classes of antibiotics being introduced. This highlights how challenging antibiotic discovery can be.

Today only a handful of larger pharmaceutical companies have active antibiotic R&D programs. The reasons as to why big pharma have abandoned this sector include low success rates, poor financial returns and difficult regulatory environments.  

Most antibiotics currently used in the clinic are synthetic derivatives of existing compounds first discovered over 50 years ago. Whilst this provides a short-term solution, these synthetic derivatives are often subject to existing resistance mechanisms and hence, quickly succumb to resistance.

Therefore we need to discover new antibiotics classes with unique chemical structures, new modes of action and that are not subject to existing resistance mechanisms.

Two of the predominant methods that have been employed in drug discovery are phenotypic screening and target-based screening.

Phenotypic screening for bioactive compounds that kill bacteria has been the mainstay for antibiotic discovery for the past century and has recently found favour again in many programmes. It is attractive as researchers can immediately identify chemicals with antibacterial activity. However the mechanism of action for the bioactive compounds must be addressed before further development can proceed and is an important hurdle to overcome.

Target-based screening approaches took over with the birth of high-throughput screening technologies that use a pre-defined target protein or enzyme to screen compound libraries. Using structural biology and drug design, compounds that bind to the target can quickly enter medicinal chemistry programmes for chemical optimisation.

Target based approaches have been tremendously successful for cancer research but underwhelming in the antibiotic field.

Both approaches have their advantages and disadvantages but no single method alone has been able to solve the antibiotic resistance problem.

One solution is to combine the best features of both phenotypic and target based-screening into modern antibiotic R&D. This is a highly specialised area of research that still requires exploration and fostering.

Many small academic research laboratories carry out early stage antibiotic discovery and are a breeding ground for fundamental research and innovative new ideas. However, these groups often lack the expertise and resources to develop their technologies to an investor ready stage.

Government sponsored programmes that help link academia with industry partners should be encouraged. Governments alone should not be burdened with supporting new antibiotic research with investors, philanthropists and industry partners playing key roles in helping to leverage more investment into the sector.

This has to be a global effort as, in the end, the world needs new antibiotics.